3-chloro dihydrodibenzazepine derivatives

ABSTRACT

New dibenzazepine derivatives of the formula   WHEREIN R is Cl, OCH3, CH3, or COCH3, and -N(R1) (R2) is dimethylamino or piperidino, as well as pharmaceutically acceptable acid addition salts thereof, are useful as psychotropic agents.

United States Patent Nakanishi et al.

[ June 6,1972

[54] 3-CHLORO DIHYDRODIBENZAZEPINE DERIVATIVES [72] Inventors: Michio Nakanishi, Oita; Chiaki Tashlro, Fukuoka, both of Japan Yoshitorni Pharmaceutical Industries, Ltd., Osaka, Japan [22] Filed: Feb. 3, 1969 [211' Appl.No.: 796,163

[73] Assignee:

[51] Int. Cl. ..C07d 41/08 [58] Field of Search ..260/294 A [56] References Cited UNITED STATES PATENTS 3,313,810. 4/1967 Nakanishi et al. ..260/243 3,329,683 7/1967 Nakanishi et a1. ..260/293 Primary Examiner-Henry R. Jiles Assistant Examiner-G. Thomas Todd Attorney-Wenderoth, Lind & Ponack ABSTRACT New dibenzazepine derivatives of the formula N CONH: l I R wherein R is Cl, OCH;,, CH, or COCH;, and -'N(R) (R is dimethylamino or piperidino, as well as pharmaceutically acceptable acid addition salts thereof, are useful as psychotropic agents.

5 Claims, No Drawings 3-CHLORO DIHYDRODIBENZAZEPINE DERIVATIVES This invention relates to new dibenzazepine derivatives of the formula:

wherein R is Cl, OCH,,, CH, or COCH and -N(R) (R is dimethylamino or piperidino, and as well as pharmaceutically acceptable acid addition salts thereof. v

The object of the present invention is to provide novel dibenzazepine derivatives of the above cited formula (I) or pharmaceutically acceptable acid addition salts thereof, which are useful, for example, as psychotropic agent. Pharmaceutical compositions are also provided.

Another object of the present invention is to provide a method of the production of the aforesaid novel and useful dibenzazepine derivatives.

The above-mentioned objects are realized (i) by reacting a compound of the formula:

C O N112 wherein M is H or alkali metal (e.g. Na) with a compound of the formula:

wherein Q is a reactive radical (e.g. a halogen, such as Cl, Br

or I, or a reactive acid residue, suchas methyl sulfonyloxy, p-

tolylsulfonyloxy), or (ii) by reacting a compound of the for- (Q being the same as above mentioned) with a compound of the formula N(R R CONH:

tion conditions. Acid acceptors such as alkali amides, alkali hydroxides, alkali carbonates and amines (e.g. triethylamine, pyridine) may be used. An excess of the starting piperidine compound may also serve as an acid acceptor.

' Thus-produced dibenzazepine derivatives represented by the formula (1) can fon'n pharmaceutically acceptable acid addition salts with various inorganic and organic acids such as hydrochloric, hydrobromic, nitric, phosphoric, sulfuric, sulfamic, oxalic, maleic, fumaric, succinic, citric, tartaric, salicylic, methanesulfonic, o-(p-hydroxybenzoyl)benzoic acid and so on.

Dibenzazepine derivatives represented by the formula (1) as well as their pharmaceutically acceptable acid addition salts, are useful as psychotropic agents. For example, in schizophrenia, the compounds of the present invention improve lack of rapport, deficiency of initiative and autism, and alleviate depressive state. The following animal tests were carried out in an attempt to compare the pharmacological actions of 3-chloro-5-(3-(4-carbamoyl-4-piperidinopiperidino)propyl)-10, 1 1-dihydro5H-dibenz( b,f)azepine di(hydrogen maleate) (hereinafter called Y-4153) with those of N-(3-(4-carbamoyl-4-piperidinopiperidino)propyl)- 10,1 1- dihydro-5l-l-dibenz( b,f)azepine dihydrochloride monohydrate (called Carpipramine) and N( 3-dimethylaminopropyl)- l 0,1 ldihydro-5H-dibenz(b,f)azepine hydrochloride (called imipramine).

Effect on locomotor activity The effect was tested by the method of PB. Dews (Brit. J. Pharmacol. 8 46, 1953). Groups each of five male mice, dd strain weighing 20 to 25 g., were kept in compartments to count their locomotor activity for 20 minutes. The test compound had been administered intraperitoneally 40 minutes before the test. The locomotor counts of control groups in 20 minutes were 247 i 51 (mean 1 standard deviation). The dose necessary to reduce the locomotor counts to is expressed as ED ED,,,,,( dose mgJKg.)

Y-4153 2.5-5 Carpipramine 2.5 lmipramine a 20 Effect on the suppression of fighting behavior Fighting episodes were produced in mice by the method of Tedeschi et al (J. Pharm. Exptl. Therap., 125, 28, 1959). Groups each of six (three pairs) dd-strain male mice, weighing 20 to 25g., were kept in an apparatus consisting of a grid floor, and were delivered an electrical stimulation of rectangular current of 1.3 milliamperes, 530 volts, 10 cycles per second stimulus intensity (for 3 minutes).

Pairs of mice treated with the test compound exhibiting 3 fighting episodes or less within 3 minutes of footshock were designated as negative responders.

The ED was calculated from the means of the inhibitory rate obtained hourly for 5 hours after the oral administration of the test compound.

The control mice of 81 pairs had the fighting episodes of 8.7 times on the average under the same condition.

ED (dose.mg/Kg.body weight) Male guinea pigs, weighing 400 to 600g.,'were used after 18 hours of fasting. The animal was killed by the blow on the neck to isolate their ileum.

The isolated ileum was suspended in 10 ml. (tissue) bath containing Tyrode's solution at 37 C, gassed with air and contractions of the ileum induced by cumulative dose of histamine were recorded on kymograph with an isotonic frontal-writing lever.

The test compound was administered preliminarily for 3 minutes before the agonist. pA and pD values of the test compound was calculated by the method of .l.M. van Rossum. (Arch. interm. Pharmacodyn, 143, 299, 1963).

p z P 2 Y4 l 5 3 5.8 Carpipramine 5.3 lmipramine 7.2 5.2

Acute toxicity The test compound was administered (intravenously (i.v.), intraperitoneally(i.p.), subcutaneously(s.c.) and orally (p.o.) to dd-strain mice and Wistar strain rats, weighing 20 to 25g. and 100 to 130g, respectively. The LD,., and fiducial limit (p=0.05) were calculated from the lethality within 7 days by Test compounds were administered to Wistar strain rats weighing about 150g. and *conditioned stimulus was delivered 4 times for 90 seconds each 1,2,3 and hours later. ED was calculated from the average inhibitory rate.

" conditioned stimulus; a buzzer unconditioned stimulus: direct current, 28V, 1.6mA.

Dose inhibitory rate mg/Kg.(i.p.)

Y-4 l 53 Carpipramine Chlorprolmipramine mazine I0 20 26 11 100 40 70 40 4.6 ED, 29 40 2.8 40

Y-4153 showed deconditioning effect about l/lO as potent as that of Chlorpromazine (N-( 3-dimethylaminopropyl)-3- chlorophenothiazine hydrochloride).

Antiapomorphine effect in rats Dose 1) Appearing rate of gnawing reflex rats mg/Kg.(p.o.) against test rats Y-4 l 53 Carpipramine TF Chlorprolmipramine mazine 40 10/10 10/10 10/10 ED 40 40 Ca. 5 40 dose mg/Kg.

body weight l. The test compound was administered 60 minutes before the use of apomorphine.(1.25mg/Kg.(i.v.)). ED was calculated from the average inhibitory rate of the appearing rate of gnawing reflex which was observed 5 and 20 minutes, respectively after the oral administration of apomorphine against groups each of 5 male rats of Wistar strain weighing about 200g. Y- 4153 as well as Carpipramine and lmipramine did not show antiapomorphine effect in rats.

Influence on pressor effects.

amines used:

Noradrenaline( N.A.) Adrenaline(Ad. Acetylcholine (Ach.) and Histamine (His.).

The influence of the test compounds upon pressor effects of amines was examined 15 minutes after administration of 5mg. of test compounds per Kg. of eight rabbits weighing 3 to 4 Kg. and was shown as minus changing rate of pressor in comparison with that of rabbits before administration.

Number of Changing rate Animals N.A. Ad. Ach. His.

Y4153 2 75.6 86.0 1l.0 22 Carpipramine 3 -69.8 57.0 10.3 25

Dose mg/Kg.p.o. Symptoms Hardly changed.

Slightly reduced locomotor activity about 60 minutes after administration. The activity recovered to normal after 24 hours. No remarkable abnormalities except the above.

Reduction of locomotor activity after 30 minutes and slight palpebral ptosis. Such sedative state continued more than 7 hours and returned to normal after 24 hours.

Obvious palpebral ptosis and reduced frequency of respiration after 10 minutes. Lowered body temperature, and about 3 hours after administration, disappeared pinnal reflex. Almost normal response to touching stimulus although slightly dull.

Remarkable palpebral ptosis and reduction of frequency of respirationv After 60 to minutes, disappeared locomotor activity with no or little sign of its recovery even by sound or touching stimulus. Slightly catatonic but no paralytic forced walk. After 15 to 18 hours, sedation in normal posture, lowering of body temperature and slight palpebral ptosis remained, but general symptoms almost recovered to normal.

Carpipramine Dose mg/Kg.p.o. Symptoms Thus, the compounds of the present invention have Carpiprarnine or imipramine-like effect to some extent but, they show a specific effect not observed in the latter two compounds.

The compound (1) of this invention and pharmaceutically acceptable acid addition salts thereof can be administered safely per se as psychotropic agent or in the form of a pharmaceutical composition in admixture with a suitable and per se conventional carrier or adjuvant, administrable orally without causing harm to the host.

The pharmaceutical composition can take the form of tablets, granules, powders, capsules, etc. for oral administration.

The choice of carrier is determined by the preferred form of administration, the solubility of the compounds and standard pharmaceutical practice. The following are examples of formulation when a compound of the present invention is administered for the pharmaceutical purposes.

(A) 25 mg. Capsule Y-4l53 29.2582 mg. (equivalent to 25 mg. of the base) lactose 105.3418 Metolose 0.4000 carboxymethylcellulose (free acid) 3.5000 magnesium steai-ate 1.5000

(B) 25 mg. Tablet product of the Shin-Etsu Chemical Industry Co., Ltd, a methylcellulose which is methylated at approximately two of the three hydroxyl groups of the glucose unit, a modified methylcellulose which in the main methylated and partly hydroxypropylated at two ofthe three hydroxyl groups ofthe glucose unit.

Usually daily dose of the compound (I) or salt thereof, lies in the range of about 50 to 700 milligrams, more practically about 75 to 300 milligrams per human adult. Thus, in case of capsules or tablets each containing 25 milligrams of compound (l) or salt thereof, three to twelve capsules or tablets per day are administered.

1n the following illustrative examples, g." stands for gram(s)" and ml. for milliliter(s)".

EXAMPLE 1 A mixture of 5.0g. of 3-chloro-5-(3-chloropropy1)-10,11- dihydro-5H-dibenz(b,f)azepine, 5.03. of 4-carbamoyl-4 piperidinopiperidine and 50 ml. of dimethylformamide is heated at C for 10 hours. The solvent is distilled off. After the addition of a 2 percent sodium carbonate solution to the flask, the content is scratched to yield a semisolid, which is dissolved in 50 ml. of isopropanol. A solution of 5g. of maleic acid in 50 ml. of isopropanol is added, and the precipitate is collected by filtration and recrystallized from isopropanol to give 5.6g. of crystalline 3-chloro-5-( 3-(4-carbamoyl-4- piperidino-piperidino )propyl l 0, 1 l-dihydro-S H dibenz( b,f)azepine di(hydrogen maleate)with 1/2 molecule of water of crystallization meltin at 181 to 183 C.

By the procedure of Example 1, 6.8g. of 3-chloro-5-( 3- chloropropyl)- l 0, 1 1-dihydro-5H-dibenz( b,f)azepine is reacted with 6g. of 4-carbamoyl-4-dimethylamino-piperidine to give 4.8g. of crystalline 3-chloro-5-( 3-(4-carbamoyl-4- dimethylaminopiperidinopropyl)-10,1 l-dihydro-S l-ldibenz(b,f)azepine di(hydrogen maleate) melting at to C.

In the same manner as in Example 1, the following dibenzazepine derivatives are also produced. 3. 3-methoxy-5 3-( 4-carbamoyl-4-piperidinopiperidino propyl)-10,1 1-dihydro-5H-dibenz(b,f)azepine di( hydrogen maleate) melting at 186C, 4. 3-acetyl-5-( 3-( 4-carbamoyl-4-piperidinopiperidino propyl)- 10,1 l-dihydro-5l-1-dibenz( b,f)azepine dihydrochloride monohydrate melting at 240 to 245 C, and 5. 3-methyl-5-( 3-(4-carbamoyl-4-piperidinopiperidino)- propyl)-10,1 1-dihydro-5H-dibenz(b,f)azepine dihydrochloride monohydrate melting at 260 to 263 C.

What is claimed is:

l. A compound of the formula N CONHz wherein -N(R) (R is a member selected from the group consisting of dimethylamino and piperidino.

2. A pharrnaceutically acceptable acid addition salt of a compound as defined in claim 1.

3. A compound as claimed in claim 1, wherein the pharmaceutically acceptable addition salt is hydrogen maleate.

4. A compound according to claim 1, namely, 3-chloro-5-(3 -(4-carbamoyl-4-piperidinopiperidino)propyl)-10,1 1- dihydro-5l-l-dibenz(b,f)azepine.

5. A compound according to claim 1, namely, 3-chloro-5-(3 8(4-carbamoyl-4-dimethy1aminopiperidino)propyl)-l0,1 l dihydro-5lrl-dibenz(b,f)azepine. 

2. A pharmaceutically acceptable acid addition salt of a compound as defined in claim
 1. 3. A compound as claimed in claim 1, wherein the pharmaceutically acceptable addition salt is hydrogen maleate.
 4. A compound according to claim 1, namely, 3-chloro-5-(3-(4-carbamoyl-4-piperidinopiperidino)propyl)-10,11-dihydro-5H -dibenz(b,f)azepine.
 5. A compound according to claim 1, namely, 3-chloro-5-(3 delta (4-carbamoyl-4-dimethylaminopiperidino)propyl)-10,11-dihydro-5H -dibenz(b,f)azepine. 